Common side effects include bone marrow suppression, liver and kidney problems, nausea, fever, rash, shortness of breath, mouth sores, diarrhea, neuropathy, and hair loss.[2] Use during pregnancy will likely result in harm to the baby.[2] Gemcitabine is in the nucleoside analog family of medication.[2] It works by blocking the creation of new DNA, which results in cell death.[2]

Taking gemcitabine can also affect fertility in men and women, sex life, and menstruation. Women taking gemcitabine should not become pregnant, and pregnant and breastfeeding women should not take it.[15]

Gemcitabine is a chemotherapy drug that works by killing any cells that are dividing.[10] Cancer cells divide rapidly and so are targeted at higher rates by gemcitabine, but many essential cells divide rapidly as well, including cells in skin, the scalp, the lining of the stomach, and bone marrow, resulting in adverse effects.[16]:265

Gemcitabine is hydrophilic and must be transported into cells via molecular transporters for nucleosides (the most common transporters for gemcitabine are SLC29A1 SLC28A1, and SLC28A3).[18][19] After entering the cell, gemcitabine is first modified by attaching a phosphate to it, and so it becomes gemcitabine monophosphate (dFdCMP).[18][19] This is the rate-determining step that is catalyzed by the enzymedeoxycytidine kinase (DCK).[18][19] Two more phosphates are added by other enzymes. After the attachment of the three phosphates gemcitabine is finally pharmacologically active as gemcitabine triphosphate (dFdCTP).[18]

When gemcitabine is incorporated into DNA it allows a native, or normal, nucleoside base to be added next to it. This leads to “masked chain termination” as gemcitabine is a “faulty” base, but due to its neighboring native nucleoside it eludes the cell's normal repair system (base-excision repair). Thus, incorporation of gemcitabine into the cell's DNA creates an irreparable error that leads to inhibition of further DNA synthesis, and thereby leading to cell death.[2][18][19]

The form of gemcitabine with two phosphates attached (dFdCDP) also has activity; it inhibits the enzyme ribonucleotide reductase (RNR), which is needed to create new nucleotides. The lack of nucleotides drives the cell to uptake more of the components it needs to make nucleotides from outside the cell, which increases uptake of gemcitabine as well.[2][18][19][20]

The synthesis described and pictured below is the original synthesis done in the Eli Lilly Company labs. Synthesis begins with enantiopure D-glyceraldehyde (R)-2 as the starting material which can made from D-mannitol in 2–7 steps. Then fluorine is introduced by a "building block" approach using ethyl bromodifluroacetate. Then, Reformatsky reaction under standard conditions will yield a 3:1 anti/syn diastereomeric mixture, with one major product. Separation of the diastereomers is carried out via HPLC, thus yielding the anti-3 gemcitabine in a 65% yield.[21][22] At least two other full synthesis methods have also been developed by different groups.[22]

Illustrates the original synthesis process used and published by Hertel et al. in 1988 of Lilly laboratories.

During the early 1990s gemcitabine was studied in clinical trials. The pancreatic cancer trials found that gemcitabine increased one-year survival time significantly, and it was approved in the UK in 1995[10] and approved by the FDA in 1996 for pancreatic cancers.[3] In 1998, gemcitabine received FDA approval for treating non-small cell lung cancer and in 2004, it was approved from metastatic breast cancer.[3]

By 2008, Lilly's worldwide sales of gemcitabine were about $1.7 billion; at that time its US patents were set to expire in 2013 and its European patents in 2009.[25] The first generic launched in Europe in 2009,[5] and patent challenges were mounted in the US which led to invalidation of a key Lilly patent on its method to make the drug.[26][27] Generic companies started selling the drug in the US in 2010 when the patent on the chemical itself expired.[27][6] Patent litigation in China made headlines there and was resolved in 2010.[28]

Because it is clinically valuable and is only useful when delivered intravenously, methods to reformulate it so that it can be given by mouth have been a subject of research.[29][30][31]

Research into pharmacogenomics and pharmacogenetics has been ongoing. As of 2014, it was not clear whether or not genetic tests could be useful in guiding dosing and which people respond best to gemcitabine.[18] However, it appears that variation in the expression of proteins (SLC29A1, SLC29A2, SLC28A1, and SLC28A3) used for transport of gemcitabine into the cell lead to variations in its potency. Similarly, the genes that express proteins that lead to its inactivation (deoxycytidine deaminase, cytidine deaminase, and NT5C) and that express its other intracellular targets (RRM1, RRM2, and RRM2B) lead to variations in response to the drug.[18] Research has also been ongoing to understand how mutations in pancreatic cancers themselves determine response to gemcitabine.[32]

It has been studied as a treatment for Kaposi sarcoma, a common cancer in people with AIDS which is uncommon in the developed world but not uncommon in the developing world.[33]